The purpose of the research program is to discover new drugs for treatment of human diseases, especially HIV/AIDS, inflammatory diseases, and cancer, and to develop faciliatory computational methods. The approach combines state-of-the-art technology for molecular design, synthetic organic chemistry, biological assaying, and structural biology, i.e., crystallographic determination of structures of the designed molecules bound to their protein targets by X-ray diffraction. The PI's group has developed computational tools to speed lead optimization for potency, while being mindful of the need for desirable pharmacological properties. Lead discovery is facilitated with the ligand-growing program BOMB, and lead optimization is guided by free-energy perturbation (FEP) calculations using Monte Carlo (MC) statistical mechanics or molecular dynamics (MD) in simulations of the unbound ligands and protein-ligand complexes in water. The viability of the approach has been well established through the discovery of numerous potent inhibitors of multiple proteins. The specific biomolecular targets are HIV-1 reverse transcriptase (HIV-RT) and macrophage migration inhibitory factor (MIF). Small organic molecules are discovered that impede HIV replication or inhibit the tautomerase activity and cytokine signaling of MIF. For HIV, rapid mutation of the virus and drug toxicity are concerns for the long-term efficacy and safety of current combination therapies. The new drug candidates are being designed to be effective against problematic variants of the virus and to have auspicious properties including solubility to facilitate oral formulation. Several classes of promising inhibitors were discovered during the las grant period; however, the catechol diether class is particularly outstanding and is the focus of additional investigations. For MIF, substantial progress has also been made with the recent report of biaryltriazoles as the most potent known tautomerase inhibitors, again with good aqueous solubility. Additional exploration of related compounds is planned along with optimization of a new class of structurally distinct MIF inhibitors, referred to as pyrazoles. For both targets, the progress and interpretation of activity data have been greatly enhanced by the acquisition of multiple high-resolution crystal structures of protein-inhibitor complexes. In addition, there continue to be numerous technical advances for computing free energies of binding for the complexes, which are used to guide the selection of molecules to synthesize and test. The progress is both in the representation of the energetics of the systems and in the exploration of alternative atomic arrangements.